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  13th International Workshop on Clinical Pharmacology of HIV Therapy
Barcelona, Spain
April 16-18, 2012
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Switching to QUAD After Atripla Has No Telling Impact on Elvitegravir Levels
  13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
Concentrations of the integrase inhibitor elvitegravir, a component of the 4-in-1 antiretroviral QUAD tablet, remained in a range consistent with potent anti-HIV activity in healthy volunteers after a switch from Atripla [1]. Efavirenz, the key component of Atripla, has the potential to interact with elvitegravir and other CYP3A and UGT1A1/3 substrates, but the impact of efavirenz on elvitegravir was not clinically meaningful in this study.
If QUAD (elvitegravir/cobicistat plus tenofovir/emtricitabine) is licensed, some people with poor efavirenz tolerance may switch from Atripla (efavirenz plus tenofovir/emtricitabine) or other efavirenz regimens to QUAD. That raises concerns because efavirenz has a long half-life and a potentially sustained impact on drugs like elvitegravir that are metabolized via the CYP3A enzyme and UGT1A1/3 (even though cobicistat inhibits CYP3A). Efavirenz induces both CYP3A and UGT. Also, efavirenz exposure may remain higher after the nonnucleoside is stopped in people with a genetic predisposition to poor metabolism via CYP2B6.
To assess the potential for unwanted interactions between lingering efavirenz concentration and elvitegravir after an Atripla-to-QUAD switch, Gilead Sciences investigators planned this study in 32 healthy volunteers, 8 of whom were poor CYP2B6 metabolizers. Everyone took QUAD (150/150/200/300 mg of EVG/COBI/FTC/TDF) once daily on study days 1 to 7. After 7 days without dosing, they took standard-dose Atripla on days 15 to 28. On day 29 they switched to QUAD, which they continued through day 62. The investigators compared elvitegravir concentrations on days 35 and 42 with concentrations on day 7.
The study group consisted of 16 men and 16 women, including 22 whites and 10 blacks. Age averaged 38 and ranged from 22 to 45. Weight averaged 74 kg and ranged from 53.4 to 102.7 kg. Five men and 3 women were poor CYPB6 metabolizers.
Three people dropped out of the study, two while taking QUAD. One of those QUAD dropouts resulted from grade 1 vomiting, and one resulted from grade 3 flank pain and lower abdominal pain. The third person quit with a grade 2 rash while taking Atripla. No other grade 3 or worse problems arose during the study.
Elvitegravir concentrations were lower after the switch from Atripla (on days 35 and 42) than before the switch (on day 7). On day 35 geometric mean ratios (GMR) and 90% confidence intervals (CI) comparing elvitegravir postswitch with preswitch were 63.1 (59.8 to 66.6) for area under the concentration-time curve (AUC), 81.5 (76.0 to 87.4) for maximum concentration (Cmax), and 32.8 (28.3 to 38.1) for trough concentration (Ctau). On day 42 respective GMRs (and 90% CIs) were 70.8 (67.2 to 74.7), 88.7 (82.7 to 95.1), and 44.5 (38.6 to 54.4). AUCs of elvitegravir's glucuronidated metabolite, GS-9200, were 46% higher on postswitch day 35 and 32% higher on postswitch day 42 than before the switch.
Elvitegravir troughs were about 3-fold above 45 ng/mL, the protein binding-adjusted 95% inhibitory concentration (IC95), on postswitch day 35 and about 5-fold above that level on day 42. Five weeks after the switch from Atripla, elvitegravir troughs were 7- to 8-fold above the IC95, or about 25% lower than the elvitegravir trough before the switch.
Cobicistat Ctau was 35% lower 2 weeks after the switch than before, but all other cobicistat levels were similar before and after the switch. Tenofovir and emtricitabine exposures were similar before and after the switch from Atripla.
Overall efavirenz exposures were similar to those of historical controls. But CYP2B6 poor metabolizers had 125% higher efavirenz AUC and 91% higher efavirenz Cmax, and postswitch elvitegravir and cobicistat concentrations were lower in poor metabolizers. Efavirenz troughs remained above 1000 ng/mL for 3 days in everyone after they stopped Atripla and above 10 ng/mL (the 90% inhibitory concentration) for 4 weeks.
A phase 3b trial assessing a switch from a nonnucleoside plus tenofovir/emtricitabine (including Atripla and Complera) to QUAD is under way in people with HIV [2].
1. Ramanathan S, Wang H, Custodio J, et al. Pharmacokinetics of EVG/COBI/FTC/TDF single tablet regimen following treatment with EFV/FTC/TDF (Atripla) in healthy subjects. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_21.
2. ClinicalTrials.gov. Phase 3b open label study to evaluate switching from regimens consisting of a non-nucleoside reverse transcriptase inhibitor plus emtricitabine and tenofovir DF to the elvitegravir/cobicistat/emtricitabine/tenofovir DF single-tablet regimen in virologically suppressed, HIV-1 infected patients. http://www.clinicaltrials.gov/ct2/show/NCT01495702.